Glaucoma is a group of progressive optic neuropathies that together are leading causes of irreversible vision loss. The pathogenic mechanisms that lead to its hallmark, progressive retinal ganglion cell (RGC) death, are unknown, but key risk factors include increased intraocular pressure (IOP). Vision loss often persists with current IOP-lowering treatments, thus urgent needs exist both for better understanding of glaucomatous mechanisms and improved glaucoma therapies other than IOP reduction. Based on our clinical findings that vision is preserved markedly longer in dogs with open-angle glaucoma (OAG) caused by spontaneous mutation of the matrix metalloproteinase-encoding gene ADAMTS10 than in dogs with other forms of glaucoma, and our novel biomechanical findings, I hypothesize that inter-individual differences in biomechanical effects of IOP on optic nerve head (ONH) contribute strongly to glaucoma progression and individuals' differential susceptibilities to it. My long-term goal is to develop novel therapeutic approaches to modify ONH and scleral biomechanics, to permit and improve preservation of optic nerve (ON) and RGC function in glaucoma patients. This multidisciplinary, collaborative translational study will test the central hypothesis that ADAMTS10-mutant individuals have high compliance of ONH, peripapillary sclera, and extracellular matrix (ECM) preceding and during glaucoma development, that protects ON axons even when IOP is chronically elevated. Specific Aims: Using clinically-relevant translational canine chronic glaucoma models, including ADAMTS10-OAG, I propose 3 Aims: In Aim 1, I will test the hypothesis that that ADAMTS10 mutation mitigates IOP-induced ON damage. In Aims 2 and 3, I will test the hypotheses that ONH and peripapillary sclera in eyes with ADAMTS10-OAG (Aim 2: tissue level) and the peripapillary scleral fibroblasts, astrocytes, and lamina cribrosa (LC) cells, and their ECM exhibit more compliant properties (Aim 3: cellular and ECM level). In addition, in Aim 3, I will test if ECM derived from ADAMTS10-mutant LC cells and peripapillary scleral fibroblasts modulates biomechanical properties of non-mutant cells. Significance: Based on extensive preliminary data and using large animal spontaneous glaucoma models, we will provide the first test of the effects of inherently-altered biomechanical properties of peripapillary sclera and ONH, and their potential interactions with elevated IOP, in determining the course of glaucoma progression. Innovation: I will determine 1) novel neuroprotective biomechanical properties of the ONH and peripapillary sclera in glaucoma in `real disease' models, and 2) compliance of astrocytes, LC cells, scleral fibroblasts, and their ECM and cell- ECM interactions in pathogenic mechanisms. My innovation includes our novel, well-established cross- disciplinary collaborative mentoring team with a strong track record in successful translational research in ocular biomechanics and genetics. Overall, findings from this proposal could introduce new and translatable therapeutic targets to preserve ON axons in glaucoma.